Aspirin: The mechanism of action revisited in the context of pregnancy complications
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1
Universidad de Antioquia, Facultad de Medicina, Grupo de Reproducción, Colombia
Aspirin, acetylsalicylic acid, is classified among the nonsteroidal anti-inflammatory drugs. These agents reduce the signs and symptoms of inflammation and exhibit a broad range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. The traditional mechanisms of low-dose aspirin (e.g. 75 to 100 mg/day) are sufficient to irreversibly acetylate serine 530 of cyclooxygenase (COX)-1, inhibiting platelet generation of thromboxane A2, resulting in an antithrombotic effect. Intermediate doses of aspirin (650 mg to 4 g/day) inhibit COX-1 and COX-2, blocking prostaglandin production, and have analgesic and antipyretic effects.
Low doses of aspirin are widely used in the prevention and treatment of diverse alterations of gestation. Currently it is accepted to prescribe low-dose aspirin to pregnant women who are at high risk for preeclampsia because it reduces the risk of this complication, as well as preterm birth and intrauterine growth restriction. Another pregnancy complication in which low-dose aspirin is recommended, is pregnancy loss associated with antiphospholipid syndrome. These women are treated with low-dose aspirin, either alone or in combination with low molecular weight heparin. In our Reproduction Group, low doses of aspirin have been used to prevent recurrent spontaneous abortion and we observed a co-adjuvant effect of the treatment when it included aspirin in comparison with other schemes that did not include it.
The reduction of the biosynthesis of prostaglandins and thromboxanes by itself does not explain the wide repertoire of anti-inflammatory actions of aspirin. More recently, an alternative mechanism for aspirin-mediated resolution of inflammation has been described namely the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid that occurs by acetylation of an active site serine on COX-2 yielding first 15R-hydroxyeicosatetraenoic acid, and then ATL via transcellular biosynthesis by 5-lypooxygenases present in leukocytes. The availability of a stable analog of ATL, has stimulated investigation on its use and it has been found that similarly to endogenously-produced lipoxins, ATL promotes the resolution of inflammation and acts as antioxidant and immunomodulator. ATL blocks the generation of reactive oxygen species in endothelial cells; it is highly anti-inflammatory inhibiting cell chemiotaxis of polymorphonuclears, leukocyte–endothelial interaction, NF-κB activation, and TNF-α secretion in activated T cells. ATL also increases nitric oxide synthesis through constitutive and inducible nitric oxide synthases.
Considering that in preeclampsia and in pregnancy losses, particularly those associated with antiphospholipid syndrome, there is an underlying inflammatory and oxidative process, we tested the effect of ATL on different settings of pregnancy complications and found that ATL reduced leukocyte-endothelial cell adhesion and the production of lipid peroxidation products (TBARS) induced by plasma from preeclamptic women. On the other hand we evaluated the effects of ATL over trophoblast functions altered by antiphospholipid antibodies from women with recurrent pregnancy losses and observed that ATL restored the migration and invasion of the first trimester trophoblast cell line HTR-8/SVneo and the trophoblast-endothelial cell interactions in a model of spiral artery transformation.
Aspirin might be used based on the induction of ATL which could lead to a more rational use of this compound in pregnancy complications such as preeclampsia and pregnancy losses so as to select patients who could benefit from aspirin, the period at which to begin the treatment, and the dose to be used.
Acknowledgements
Financial support: Estrategia de Sostenibilidad Grupo Reproducción 2014-2015
Keywords:
Aspirin,
Aspirin-triggered lipoxins,
Antiphospholipid Syndrome,
Pregnancy Complications,
Immunomodulation
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Oral Presentation
Topic:
Immunology of reproduction
Citation:
Cadavid J
AP
(2015). Aspirin: The mechanism of action revisited in the context of pregnancy complications.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00089
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Received:
31 May 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
Dr. Angela P Cadavid J, Universidad de Antioquia, Facultad de Medicina, Grupo de Reproducción, Medellin, Colombia, angela.cadavid@udea.edu.co